NM_032409.3:c.388-7A>G

Variant names:

• chr1-20637835-A-G
• rs2298298
• NM_032409.3:c.388-7A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032409.3(PINK1):​c.388-7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.869 in 1,613,594 control chromosomes in the GnomAD database, including 610,562 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.84 (53986 hom., cov: 31)
  • Exomes 𝑓: 0.87 (556576 hom.)
• Consequence: PINK1 NM_032409.3 splice_region, intron
• Scores: Splicing: ADA: 0.00005242
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.271
• Publications: 26 publications found

Genes affected

PINK1 (HGNC:14581): (PTEN induced kinase 1) This gene encodes a serine/threonine protein kinase that localizes to mitochondria. It is thought to protect cells from stress-induced mitochondrial dysfunction. Mutations in this gene cause one form of autosomal recessive early-onset Parkinson disease. [provided by RefSeq, Jul 2008]

PINK1 Gene-Disease associations (from GenCC):

• autosomal recessive early-onset Parkinson disease 6

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• Parkinson disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• young-onset Parkinson disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 1-20637835-A-G is Benign according to our data. Variant chr1-20637835-A-G is described in ClinVar as Benign. ClinVar VariationId is 262027.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.872 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032409.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PINK1	NM_032409.3	MANE Select	c.388-7A>G		splice_region intron	N/A	NP_115785.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PINK1	ENST00000321556.5	TSL:1 MANE Select	c.388-7A>G		splice_region intron	N/A	ENSP00000364204.3
	PINK1	ENST00000878749.1		c.388-7A>G		splice_region intron	N/A	ENSP00000548808.1
	PINK1	ENST00000878743.1		c.388-7A>G		splice_region intron	N/A	ENSP00000548802.1

Frequencies

GnomAD3 genomes AF: 0.840 AC: 127756 AN: 152014 Hom.: 53957 Cov.: 31

Gnomad AFR AF: 0.762

Gnomad AMI AF: 0.837

Gnomad AMR AF: 0.809

Gnomad ASJ AF: 0.903

Gnomad EAS AF: 0.797

Gnomad SAS AF: 0.881

Gnomad FIN AF: 0.927

Gnomad MID AF: 0.902

Gnomad NFE AF: 0.878

Gnomad OTH AF: 0.864

GnomAD2 exomes AF: 0.862 AC: 216056 AN: 250728 AF XY: 0.867

Gnomad AFR exome AF: 0.764

Gnomad AMR exome AF: 0.809

Gnomad ASJ exome AF: 0.900

Gnomad EAS exome AF: 0.811

Gnomad FIN exome AF: 0.929

Gnomad NFE exome AF: 0.877

Gnomad OTH exome AF: 0.871

GnomAD4 exome AF: 0.872 AC: 1274335 AN: 1461462 Hom.: 556576 Cov.: 63 AF XY: 0.873 AC XY: 634662 AN XY: 727044

African (AFR) AF: 0.752 AC: 25177 AN: 33460

American (AMR) AF: 0.807 AC: 36091 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.900 AC: 23532 AN: 26136

East Asian (EAS) AF: 0.791 AC: 31394 AN: 39700

South Asian (SAS) AF: 0.882 AC: 76010 AN: 86226

European-Finnish (FIN) AF: 0.927 AC: 49516 AN: 53416

Middle Eastern (MID) AF: 0.911 AC: 5015 AN: 5504

European-Non Finnish (NFE) AF: 0.877 AC: 975166 AN: 1111926

Other (OTH) AF: 0.869 AC: 52434 AN: 60370

GnomAD4 genome AF: 0.840 AC: 127840 AN: 152132 Hom.: 53986 Cov.: 31 AF XY: 0.843 AC XY: 62669 AN XY: 74364

African (AFR) AF: 0.762 AC: 31600 AN: 41464

American (AMR) AF: 0.808 AC: 12349 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.903 AC: 3134 AN: 3472

East Asian (EAS) AF: 0.796 AC: 4117 AN: 5170

South Asian (SAS) AF: 0.881 AC: 4247 AN: 4820

European-Finnish (FIN) AF: 0.927 AC: 9822 AN: 10594

Middle Eastern (MID) AF: 0.898 AC: 264 AN: 294

European-Non Finnish (NFE) AF: 0.878 AC: 59719 AN: 68012

Other (OTH) AF: 0.865 AC: 1826 AN: 2112

Alfa AF: 0.862 Hom.: 67148

Bravo AF: 0.829

Asia WGS AF: 0.821 AC: 2856 AN: 3478

EpiCase AF: 0.880

EpiControl AF: 0.883

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	Autosomal recessive early-onset Parkinson disease 6 (3)
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.0
DANN	Benign	0.55
PhyloP100		-0.27
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000052
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2298298; hg19: chr1-20964328;